Several high profile pathogens secrete virulence factors which manipulate host cAMP levels, including Vibrio cholera, Bordetella species, Bacillus anthracis, and Pseudomonas aeruginosa. These toxins contribute to pathogenesis by repressing aspects of innate and adaptive immunity in vitro, in particular phagocytosis, chemotaxis and the production of reactive oxygen species, thereby permitting bacteria to establish infection. In this proposal, we will identify functional differences between the three primary adenylate cyclase toxins (ACT) and pharmacological stimulation of cAMP on monocytes, using a series of purified ACT variants and chimeras, cell biology techniques and transcriptional profiling. In addition, using small molecule inhibitors and over-expression of regulatory subunits, we will define the host signaling events mediating immune suppression after intoxication. Experiments outlined in this proposal will lead to a better understanding of the role of bacterial adenylate cyclase toxins in pathogenesis. [unreadable] [unreadable]